The insidious consumption of high fat diets can result in the accumulation of unutilized lipid, or visceral adiposity. Current dietary fats contain a large proportion of proinflammatory saturated fatty acids (PSFA), and proinflammatory lipid peroxides, which accumulate in adipocytes and then in other organs, including renal tubules. The ingestion of high fat diets with resulting adiposity, dyslipidemia and diabetes increases serum levels of oxidized low density lipoprotein (oxLDL). Circulating PSFA and oxLDL stimulate expression of LOX-1, a transporter that internalizes oxLDL and PSFA in renal capillaries and tubules. Once internalized, the lipids alter the normal renal endothelial phenotype into a more permeable proinflammatory phenotype. The abnormal permeability of glomerular and peritubular capillaries allows passage of macromolecules. This important clinical transition is recognized as proteinuria and accompanying toxic lipiduria, and it indicates progression to renal failure. We suggest that the now permeable albumin-bound PSFA and lipid peroxides reach and damage tubules from peritubular and luminal sides. We propose to address the role of lipids in nephropathy with the hypothesis: Oxidized lipid and saturated fatty acids activate the expression of the oxLDL receptor LOX-1, which promotes a tubular proinflammatory phenotype. We will test this hypothesis in vivo on rat and mouse models of obesity-diabetes and in vitro on rat proximal tubule NRK52E cells. We want to study the mechanism of LOX-1 activation (SA1) and the mechanism by which LOX-1 activation evokes the pro-inflammatory and pro-fibrotic phenotype in renal tubules (SA2). The rationale behind our proposal is based on the presumption that the lipid-driven conversion of proximal tubules to a pro-inflammatory state, pro-fibrogenic state, is an important mechanism of renal failure in diabetes and obesity. PUBLIC HEALTH RELEVANCE: We want to study the mechanisms by which surplus lipid damages the kidney and stimulates an inflammatory response. This is one of the major problems in diabetes- obesity that afflicts our veteran's population.